To determine whether the Th1 response in tuberculosis correlated with IL-12R expression, we measured expression of the IL-12Rβ1 and IL-12Rβ2 subunits, as well as IL-12Rβ2 mRNA expression in tuberculosis patients and healthy tuberculin reactors. In tuberculosis patients, IFN-γ production by Mycobacterium tuberculosis-stimulated PBMC was reduced, the percentages of T cells expressing IL-12Rβ1 and IL-12Rβ2 were significantly decreased, and IL-12Rβ2 mRNA expression was also markedly reduced. In contrast, in pleural fluid and lymph nodes at the site of disease in tuberculosis patients, in which IFN-γ production is enhanced, IL-12Rβ2 mRNA expression was also increased. In M. tuberculosis-stimulated peripheral blood T cells from tuberculosis patients, anti-IL-10 and anti-TGF-β enhanced IL-12Rβ1 and IL-12Rβ2 expression, and IFN-γ production. In M. tuberculosis-stimulated peripheral blood T cells from healthy tuberculin reactors, recombinant IL-10 and TGF-β reduced IL-12Rβ1 and IL-12Rβ2 expression, as well as IFN-γ production. In combination with prior studies showing increased production of TGF-β by blood monocytes from tuberculosis patients, this suggests that increased TGF-β production is the underlying abnormality that reduces IL-12Rβ1 and IL-12Rβ2 expression in tuberculosis. Our findings provide evidence that IL-12R expression correlates well with IFN-γ production in human tuberculosis, and that expression of IL-12Rβ1 and IL-12Rβ2 may play a central role in mediating a protective Th1 response.